Technical Field
The present disclosure relates to a moisture curable polymer that is biocompatible and suitable for use in surgical applications and radiotherapy as a fiducial marker, a tissue spacer, or a brachytherapy seed spacer and marker.
Description of the Related Art
The “background” description provided herein is for the purpose of generally presenting the context of the disclosure. Work of the presently named inventors, to the extent it is described in this background section, as well as aspects of the description which may not otherwise qualify as prior art at the time of filing, are neither expressly or impliedly admitted as prior art against the present invention.
Conventional radiotherapy aims to control tumor infiltration, whereas surgery is sometimes necessary to control the bulky tumor volume. Modern radiotherapy delivery techniques can control both tumor infiltration and the bulky tumor by irradiating tumors with higher doses of radiation and greater spatial selectivity (localization) thus sparing surrounding normal tissues from radiation damage. In order to control tumor infiltration, the treatment beam needs to be accurately positioned with respect to the tumor. In recent years, image-guided radiotherapy (IGRT) has been integrated into the majority of radiotherapy treatment delivery machines. IGRT is currently a key component of modern radiotherapy treatments. Conventional approaches to image guidance involve preoperative images (mainly CT scans) registered (i.e. image correlation to field of view) intra-operatively to the reference frame of the patient and navigation system by co-localization of fiducial markers affixed to the patient. At least three (and commonly six to 12) fiducials are necessary to provide accurate registration. The navigation system can then provide a virtual representation of tools in real-time within the context of the preoperative image data.
Recent advancements in IGRT have allowed for the increase in radiation (also known as dose escalation) dose delivery to malignant tumors leading to better tumor control than ever before. However, the downside of dose escalation is the potential increase in toxicity to adjacent organs at risk. One typical example is the potential rectal damage as a result of dose escalation in prostate radiotherapy in which the rectum is considered a sensitive critical surrounding structure. In order to minimize toxicity in dose escalation regimens, inter- and intra-fractional target motion must be taken into account before the delivery of the radiation dose. Organs such as the prostate are susceptible to deformation and motion which can be attributed to physical internal organ movements, breathing, weight loss and uncertainties related to patient setups. Accounting for these motion-related deviations would allow the delivery of the desired dose coverage of the target volumes whilst minimizing unnecessary dose to normal organs. Further, accounting for the deviations would allow a physician to prescribe tighter treatment margins around the tumor, possibly reducing the dose to normal tissues.
Due to the increase in IGRT treatments, various techniques have been explored to assist in tracking the location of tumors and surrounding critical structures. The most commonly used technique involves implantation of fiducial markers as surrogates of the target volumes with the linear accelerator (LINAC) built-in kilovoltage or megavoltage imaging systems. However, computed tomography (CT) images are limited in terms of detail and show only information about the bony anatomical structures. For many clinical applications, the image quality of these CT scans is not sufficient to accurately distinguish the tumor from surrounding healthy tissues. This has steered an extensive research and development in the integration of magnetic resonance imaging (MRI) into modern radiotherapy treatment systems as an alternative to CT.
The use of MRI for the guidance of radiotherapy has revolutionized diagnostics imaging due to excellent soft tissue contrast. This clearly makes MRI well suited for radiotherapy, both in the definition of tumor geometry and the characterization of its functional information.
Tissue characteristics can be imaged by determining the concentration (or density) of hydrogen (H1) protons within the tissue and weighting (T1 or T2-weighted imaging). For example, tissues with high proton contents (e.g., fat) will produce strong signals and have a bright appearance on T1-weighted images. Therefore, the MR image is an image of H1 protons. When tissues that contain hydrogen (i.e., protons) are subjected to a magnetic field, some of the proton nuclei spins align in the same direction as the magnetic field. This alignment produces the magnetization in the tissue, which then emits a radio-frequency signal. Tissues that do not have an adequate concentration of hydrogen are not visible on MRI.
The MR-Linac (MRL) combines two advanced technologies—an MRI scanner and a linear accelerator—to precisely locate tumors in real-time, and adapt the shape of the X-ray beams in real time to conform to the shape of the tumor. MRL is a new technology with few prototype systems being tested for clinical use worldwide. See patents Nos: WO 2009113069A1, WO 2014044635A1, U.S. Pat. Nos. 9,155,913 B2, 8,331,531 B2, and US 20140135615 A1, each incorporated herein by reference in its entirety.
However, the location of tumors, as well as normal tissues and organs at risk inside the body, change frequently. For example, lung tumor/s will move up and down during the patient's breathing. The location of prostate tumors changes from day-to-day depending on fullness of the bowel and bladder of the patient during radiotherapy treatment. Therefore, there is still a risk of the tumor shifting location, which increases the probability of delivering unnecessary radiation dose to adjacent healthy tissues or organs.
Precise adaptive radiotherapy guided by real-time MRI images could prove a significant advance in radiation oncology in general if the daily location of tumors and its proximity to surrounding critical structures can be accurately determined. To overcome this challenge, a minimally invasive MRI-visible marker system would significantly improve the efficiency of MRI-guided radiotherapy. Such a minimally invasive MRI-visible marker will also enable the constant monitoring of tumor movement during treatment by acting as image registration surrogates for indicating the position of the treatment volumes and also, the precise targeting of moving tumors and avoidance of healthy surrounding tissues. MRI contrast depends on the biologically variable parameters of proton density; longitudinal relaxation time (T1), and transverse relaxation time (T2), variable image contrast can be achieved by using different pulse sequences and by changing the imaging parameters. Signal intensities on T1, T2, and proton density-weighted images relate to specific tissue characteristics. Therefore, a key requirement for an MRI-visible marker system is to have a different MRI signal intensity to that of normal tissues. This will enable the markers to be clearly distinguished from normal tissues and also, enable them to be used for tumor tracking and daily pre-treatment quality assurance procedures.
Further, current brachytherapy seeds and spacer technologies involves attaching a polymer (with or without encapsulated liquid contrast agent) to brachytherapy seeds by some form of adhesive such as cyanoacrylate adhesives or polymer thread such as polyurethanes. See US 20100324353 A1, Adhesive-stiffened brachytherapy strand, Kevin Helle, et al, Dec. 23, 2010; and US 20150375011, Brachytherapy Seed Insertion and Fixation System, John Spittle, Dec. 31, 2015, each incorporated herein by reference in its entirety. However, one shortcoming of such adhesive technologies is that they are fragile considering the size of the seeds and usually susceptible to breakage during the implantation process or post-implantation. Saibishkumar et al., 2009 compared stranded seeds (SSs) with loose seeds (LSs) in terms of seed loss after 125I prostate brachytherapy. See Saibishkumar E P et al., 2009 Sequential Comparison of Seed Loss and Prostate Dosimetry of Stranded Seeds With Loose Seeds in 125I Permanent Implant for Low-Risk Prostate Cancer Int. J. Radiat. Oncol. Biol. Phys. 73 61-8, incorporated herein by reference in its entirety. The preceding references observed greater seed loss with SSs compared with LSs, with the primary site of loss being the urinary tract. Therefore, a more durable seed-spacer attachment system is highly desirable to minimize breakage and migration of commercial radioactive seeds. Assigned patent application pub. No US 20140178297 A1 describes a contrast marker and a spacer comprising a liquid Cobalt-based compound [(CoCl2)n(C2H5NO2)1-n] encased in a polymer, incorporated by reference herein in its entirety. Assigned patent application pub. No U.S. Pat. No. 8,821,835B2 describes a brachytherapy spacer where therapeutic agents can be encapsulated within cylindrical shape objects. See U.S. Pat. No. 8,821,835 B2, “Flexible and/or elastic brachytherapy seed or strand,” Edward J. Kaplan, Sep. 2, 2014, incorporated herein by reference in its entirety. A polymer that can withstand the natural motion of tumors and tissues, and prevent risk due to breakage of brachytherapy seeds by creating a tight seal around the seed, is of value to the medical radiotherapy field.
In view of the forgoing, one objective of the present disclosure is to provide a biocompatible curable composition which includes metallic nanoparticles and is cured in situ upon contact with moisture to provide a fiducial marker which is visible by an imaging modality and useful in radiation therapy.